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Abstract

Background

As more point of care diagnostics become available, the need to transport and store
perishable medical commodities to remote locations increases. As with other diagnostics,
malaria rapid diagnostic tests (RDTs) must be highly reliable at point of use, but
exposure to adverse environmental conditions during distribution has the potential
to degrade tests and accuracy. In remote locations, poor quality diagnostics and drugs
may have significant negative health impact that is not readily detectable by routine
monitoring. This study assessed temperature and humidity throughout supply chains
used to transport and store health commodities, such as RDTs.

Methods

Monitoring devices capable of recording temperature and humidity were deployed to
Burkina Faso (8), Senegal (10), Ethiopia (13) and the Philippines (6) over a 13-month
period. The devices travelled through government supply chains, usually alongside
RDTs, to health facilities where RDTs are stored, distributed and used. The recording
period spanned just over a year, in order to avoid any biases related to seasonal
temperature variations.

Results

In the four countries, storage and transport temperatures regularly exceeded 30.0°C;
maximum humidity level recorded was above 94% for the four countries. In three of
the four countries, temperatures recorded at central storage facilities exceeded pharmaceutical
storage standards for over 20% of the time, in another case for a majority of the
time; and sometimes exceeded storage temperatures at peripheral sites.

Conclusions

Malaria RDTs were regularly exposed to temperatures above recommended limits for many
commercially-available RDTs and other medical commodities such as drugs, but rarely
exceeded the recommended storage limits for particular products in use in these countries.
The results underline the need to select RDTs, and other commodities, according to
expected field conditions, actively manage the environmental conditions in supply
chains in tropical and sub-tropical climates. This would benefit from a re-visit of
current global standards on stability of medical commodities based in tropical and
sub-tropical climatic zones.

Keywords:

Background

A major challenge for health systems in the tropics and sub-topics in the delivery
of health care to remote and rural populations is maintaining the quality of commodities
from time of entry to the country to time of use. Diagnostics and drugs can be subject
to prolonged storage and transport where ambient temperature and humidity are high,
while resources for environmental control are limited. The accelerated increase in
the use of malaria rapid diagnostic tests (RDTs), perishable biological tests based
on capture of parasite antigen by antibodies (protein) stabilized on a nitro-cellulose
(organic) strip, has raised the profile of this issue within many health services
in malaria-endemic regions. While emphasis on the manufacture of stable tests is essential
in addressing this [1-4], understanding and managing the subsequent transport and storage of RDTs, and matching
product stability to these conditions, is essential to ensure that misdiagnosis and
subsequent avoidable mortality do not occur.

The WHO recommends parasitological confirmation of malaria by microscopy or alternatively
by rapid diagnostic tests (RDTs) in all patients suspected of malaria before treatment
initiation [5]. As most people at risk have poor access to reliable microscopy, widespread use of
RDTs in remote, hard-to-supply areas is therefore essential to implement this policy
[6]. Typically, RDTs and other health commodities arrive at a central warehouse, from
where they may be distributed to regional or district facilities, or directly to peripheral
health facilities. Recommendations on storage and transport recommend minimizing storage
time at clinic level, but long peripheral storage may be necessary to maintain adequate
safety stocks. A previous study in South East Asia reported storage beyond RDT manufacturer
limits [7]. Such temperatures have been shown to degrade some commercially available tests [4].

Standards for registration of perishable medical commodities (drugs and in-vitro diagnostics) of the International Conference on Harmonization (ICH) and the Global
Harmonization Task Force are well defined for cooler, temperate regions (Climatic
Zones I and II) [8]. For climatic Zones III (hot/dry) and IV (hot/humid), ICH recommended a minimum stability
for 1 year at 30°C and 35% humidity (Zone III) and 30°C and 65% humidity (Zone IV)
[9]. While noting the ASEAN-recommended variant of 30°C and 75% humidity for Zone IV
[10], the WHO still endorses the former ICH guidelines for Zones III and IV for pharmaceuticals
[11], which commonly share supply lines with diagnostics. The adequacy of these standards
is crucial to malaria management, as the countries concerned are often limited in
their ability to control storage conditions. Furthermore remoteness and limits in
capacity for managing stocks often require total product life-spans of well over the
12 months on which ICH criteria are based.

This study aimed to gather data on actual temperatures and humidity levels, in different
climatic zones, to which RDTs are subjected as they move through the supply chains
that typically serve malaria-endemic countries to assess the appropriateness of RDTs
procured in each country programme in terms of thermal stability. With the wide roll-out
of RDTs in recent years and limited capacity for quality control once RDTs are dispersed
from the central warehouse, understanding the likely environment in which RDTs are
transported and stored is vital for procurement decisions and patient safety.

Methods

The study monitored temperature and humidity in storage facilities and health facilities
in four malaria-endemic countries: Senegal, Burkina Faso, Ethiopia, and the Philippines.
All are in ICH Climatic Zones III and IV [8], but have a range of climatic conditions. Temperature data collection was carried
out during storage and transport events occurring in selected sites in each country
during the study period. These were compared with the manufacturer-recommended product
storage temperatures of each product at the time of the study.

Temperature and humidity recordings

Temperatures and humidity were recorded using electronic monitors (LogTag® HAXO-8 Humidity & Temperature Recorder; ACR Systems, New Zealand, Range −40°C to
+85°C [± 0.5°C] and 0% to 100% RH [± 3 RH]). The monitors are equipped with a button
which enables users to record a “mark” in the data stream, with a corresponding date
and time, to be used when an event occurs, such as when transport left, or arrived
at, a storage facility. The monitors were sent to the field inside envelopes with
a form on the back allowing field collaborators to record relevant events. For the
purposes of this study, LogTag monitors were either stored and transported alongside
RDTs, or placed in locations where RDTs are routinely stored. The monitors were set
to capture temperature and humidity data every two hours in storage facilities, while
those specifically sent with transport were programmed to record every 30 or 60 minutes.
Stored data was downloaded from the LogTag monitors and the mean temperatures were
calculated using Microsoft Excel.

Senegal

Climate

Senegal, a coastal country extending into the arid Sahel, has a tropical climate with
dry and rainy seasons. Average annual minimum and maximum temperatures range between
18°C and 30°C on the coast and 24°C and 40°C inland, with a maximum temperature of
around 50 degrees (National Agency of Meteorology Senegal, unpublished data, 2010).

Supply chain and storage facilities

On delivery to the public sector, malaria RDTs are stored in the National Supply Pharmacy
in Dakar, a non-air-conditioned site, prior to distribution. Temperature and humidity
were monitored in the National Supply Pharmacy, two regional supply pharmacies, three
district pharmacies, three health posts and one health hut (the lowest level of public-sector
health care delivery). Transport data (by truck, car and bicycle) was collected from
the central store to peripheral stores.

Study timeline

Data was collected over 13 months, from December 2009 to January 2011.

Malaria RDT

The test used in the National Malaria Control Programme (NMCP) during the study had
a manufacturer-recommended storage temperature range from 1 to 40°C, and was detecting
HRP2 (Histine-rich protein 2) antigens (single test line).

Burkina Faso

Climate

Burkina Faso is a landlocked Sahel country with climatic zones ranging from very arid
in the north to humid in the south, with distinct dry and rainy seasons. There is
wide variation in temperatures, with an annual range between 5°C and 47°C (Institut
Géographique du Burkina, unpublished data, 2011).

Supply chain and storage facilities

Temperatures and relative humidity were monitored in the central store (CAMEG – Centrale
d’achat de Médicaments Essentiels Génériques) in Ouagadougou, one regional store where
public-sector procurement is initially received, two health district stores, and three
health center stores. Transport data (by van and truck) was collected from the central
store to regional stores (3) and from regional stores to health district stores (3).
RDTs were not kept under air-conditioning in any of these facilities.

Study timeline

Data was collected over a period of 12 months, from August 2009 to August 2010.

Malaria RDT

The RDT procured by the NMCP of Burkina Faso during the study had a recommended temperature
storage range of 1°C to 40°C; this product was targeting both pLDH (Plasmodium lactate deshydrogenase) and HRP2 antigens (two test lines).

Ethiopia

Climate

The mean annual temperatures in Ethiopia range from 10°C to 40°C, the maximum occurring
in the lowlands, while the climate is milder in the central highlands, much of which
are malaria-free [12].

Supply chain and storage facilities

Temperature and humidity were monitored in the central store (PFSA – Pharmaceutical
Fund and Supply Agency) in Addis Ababa where they were temporarily stocked before
distribution to three regional stores, three health center stores and six health posts
in the regions. None of these facilities had air-conditioning.

Study timeline

Data was collected over a period of 13 months, from December 2009 to January 2011.

Malaria RDT

The two malaria RDTs in use during this study had storage recommendations of 4°C to
30°C and 4°C to 45°C, respectively. One product targeted both pLDH and HRP2 antigens
(two test lines), while the other only HRP2 antigen (single test line).

The Philippines

Climate

The Philippines is an island country with a tropical climate and a mean annual temperature
of 26.6°C. During the hot season, temperatures rise above 36°C [13].

Supply chains and storage facilities

Temperature and humidity were monitored at the Department of Health Central Warehouse
in Manila, in two regional warehouses and at health centers in three remote villages.
None of these facilities was air-conditioned. Temperatures were also recorded during
transport direct from the Central Warehouse to two villages.

Study timeline

Data was collected over a period of 15 months, from June 2009 to September 2010.

Malaria RDT

The malaria RDTs distributed during the study had recommended storage temperatures
from 4°C to 45°C, and 4°C to 37°C, respectively. One product targeted HRP2 antigen
(single test line), and the other both aldolase and HRP2 antigens (two test lines).

Results

Storage data

Considerable variation was recorded in temperatures throughout the commodity supply
chain, with temperatures ranging from 8.3°C to 47.6°C and a maximum humidity recorded
of 100% (± 3 RH). Data are summarized in Table 1.

Senegal

Temperatures ranged from 19.2°C to 47.6°C. In three facilities, at the regional, district
level and health center level (in the regions of Matam, Nabadaji, and Ourossogui respectively),
temperatures greater than 30.0°C were recorded for more than 70.0% of the time. At
the central warehouse level in Dakar, temperatures below 30.0°C were recorded 96.9%
of the time. Temperatures were also reported to be higher in the Kolda regional warehouse
than in the pharmacy of Kounkané, and reached a maximum of 38.3°C and 37.4°C respectively.

Temperatures were particularly high at the Ourossogui regional warehouse (maximum
41.8°C) and Nabadaji Pharmacy and Health Center (maximum 47.6°C), where temperatures
above 30.0°C were recorded every week (Figure 1). Each threshold line (red lines) indicated in figures 1 and 2 represents one of
the manufacturer-recommended storage temperatures for the RDTs used in this study
(30, 37, 40, 45°C).

Figure 1.Storage temperatures across study period at 2 facilities in Senegal.

Burkina Faso

Temperatures ranged from 13.6°C to 42.7°C. In two facilities, the health district
level and health centre level in the region of Dori, temperatures higher than 37.0°C
were recorded for more than 11.8% of the total storage time. At the central warehouse
level in Ouagadougou, temperatures above 30.0°C were recorded 47.7% of the time. In
Gaoua, temperatures were higher in the health district than in the more peripheral
health centers, with maximums of 39.4°C and 35.9°C respectively.

Ethiopia

Temperatures ranged from 8.3°C to 43.7°C. In two facilities, at health center and
health post level in the region of Afar, temperatures over 40.0°C were recorded. At
the central warehouse level in Addis, temperatures were over 30.0°C for 0.9 % of the
time. In Oromia and Afar regions, higher temperatures were reported at the central
and regional warehouses than at the heath post level. Temperatures were particularly
high in Afar region where temperatures above 37.0°C were recorded over several weeks
between April and October in two health centers (Figure 2).

Figure 2.Storage temperatures across study period at 2 facilities in Ethiopia.

The Philippines

Temperatures ranged from 21.2°C to 36.4°C. At the central warehouse level in Manila,
temperatures higher than 30.0°C were recorded 23.7% of the time.

Comparison with manufacturer-recommended temperatures

In Burkina Faso, Senegal and Ethiopia storage temperatures exceeded the recommended
RDT manufacturer temperature limits. In three out of eight facilities (one health
district facility and two health centres) in Burkina Faso, temperatures rose above
the recommended RDT manufacturer temperature limit of 40°C. In 11 out of 13 facilities
in Ethiopia (one health center, six health posts, two central warehouses, two regional
warehouses), temperatures exceeded the recommended RDT manufacturer temperature limit
of 30°C, up to 80.3% of time at one site. In five out of ten facilities in Senegal
(one regional warehouse, two district pharmacies, two pharmacies/health post), temperatures
rose above the recommended RDT manufacturer temperature limit of 40°C, 18.2% of the
time in one site (Table 1).

Humidity

All RDTs are sealed in foiled packages and should not been exposed to humidity before
use, although humidity is a matter of concern only when an RDT package has been damaged.
Maximum humidity recorded ranges from 94 to 100% RH (Table 1).

Transport data

Thirty transport chains were recorded for the three countries (Senegal, Burkina Faso,
and the Philippines).

From the national to the regional warehouse level, two different transport chains
were recorded in Senegal and each transport took 25 hours (minimum 27.3°C, maximum
38.8°C). In Burkina Faso, nine different transport chains occurred and transport took
between three to nine hours (minimum 24.4°C, maximum 43°C). In the Philippines, three
transport episodes were recorded from the central and regional warehouses to health
centers in Palawan, Mindoro and Tuguegarao. These involved both road and air conveyances.
In all three cases, the average temperature remained within acceptable limits (minimum
22.1°C, maximum 29.1°C), with the exception of one transport chain segment where the
maximum temperature rose to 41.5°C. Data for all the transport chains are presented
in Table 2.

Discussion

The malaria rapid diagnostic tests monitored in this study were exposed to conditions
above manufacturer recommendations in three of the four countries studied, though
for only brief periods. However, in all countries, conditions within these supply
lines were above 30°C for considerable periods- beyond the WHO recommendations for
stability of pharmaceuticals that are delivered through similar supply chains [11], and thus for many other commercially-available malaria RDTs. While the countries
appear to have selected RDTs with stated stability, in keeping with general transport
and storage conditions in this limited survey, the results raise questions over adequacy
of supply line management for other medical commodities. In the four countries, drugs
and RDTs are stored under the same conditions; this illustrates the importance of
understanding transport and storage conditions in RDT product selection [14].

Whether the periods of temperature exposure recorded here affect RDT quality depends
on the stability of the individual products. Previous studies have shown a high variability
in RDT stability, both for HRP2 detecting test lines and particularly for test lines
detecting pLDH [1-4]. Stability can vary at times between lots of specific products [1,3,15], but real-time stability data on a range of products lot-tested through the WHO-FIND
malaria RDT evaluation programme suggests that significant failures in tests stored
within manufacturer recommendations are not common [16]. The products in use by public health services in the countries involved in this
study had maximum storage recommendations ranging from 40°C to 45°C, well above the
former ICH recommendations, but only exceeded these temperatures for relatively short
periods of time. However, these temperatures are above the recommendations for many
other malaria RDTs; only 13 of the 50 RDTs tested in the Round 3 of the WHO Product
Testing Programme had recommended storage temperatures of 40°C or above (FIND, unpublished
data).

Other commodities (with the exception of vaccines) are generally stored together in
the same facilities at central, regional, and peripheral levels. For example, certain
tablet formulations of anti-malarials (e.g., artemether-lumefantrine, artesunate,
amodiaquine, sulphadoxine, pyrimethamine), and HIV antiretrovirals (e.g., lopinavir,
ritonavir) listed as essential drugs should not be stored above 30°C [17].

These data raise a number of issues. Firstly, diagnostics (and drugs) clearly need
to be selected taking into account the expected exposure to heat and humidity. While
humidity is normally addressed by the moisture-proof packaging in which the product
is delivered, measuring temperature using electronic monitors is relatively easy and
cheap. This knowledge should inform procurement criteria. As openly-available data
on real-time stability is limited, it seems advisable for countries to require real-time
heat stability data from manufacturers on which product storage recommendations should
be based. It has been recommended to store RDTs at a central level for as long as
possible on the assumption that peripheral storage is less controlled [18]. High temperatures recorded at central facilities in the four countries suggest that
logistics planning should take actual storage data into account, and that managing
conditions at central storage facilities should be taken more seriously. While storage
standards for in-vitro diagnostic are less well defined, WHO standards for temperature stability of pharmaceuticals
were exceeded at central storage over 23% of the time in two countries [11].

Clearly, published standards for pharmaceuticals and diagnostics in these climatic
conditions are inadequate. Without substantial resources devoted to controlled transport
and storage, temperatures of 30°C are routinely exceeded. There does appear to be
a case here for investment in temperature control of central medical storage facilities.
However, RDTs are a relatively high volume commodity, making controlled-temperature
transport and storage at remote locations often impractical. Refrigeration is unnecessary
for current products, and can also pose some risks, as shown in this study where one
RDT was exposed to temperatures below −3°C in Burkina Faso. RDT storage outside the
manufacturer-recommended temperature could shorten RDT product shelf life, yet this
is difficult to detect. When RDTs are known to have been subjected to extreme conditions
for some time, re-testing a batch withdrawn from the field against parasite panels
is possible (e.g. lot testing laboratories in the Philippines and in Cambodia, [19], or comparing with microscopy, but both can be logistically difficult. Rejecting
a batch on the basis of transport conditions without evidence of poor performance
is costly. The development of positive control wells, based on lyophilized parasite
antigens, holds promise to address clinic-level quality control dilemmas for malaria
RDTs [20].

Lower cost solutions are available for remote-area storage, such as underground storage
or the use of evaporative cooler boxes [21]. Storage using evaporative cooling has been demonstrated for malaria RDTs in Afghanistan
[22] and Cambodia [23], reducing temperatures from as much as 37°C to 23°C without use of electricity, well
within the common range for storage of non-vaccine medical commodities. Moreover,
simple measures during transport, such as loading and discharging vehicles in the
shade or at night, reduce the probability of deterioration [21,24]. In the end, the performance of the product at end-user level is the most important
measure of impact of previous environmental damage; this is difficult to sustain for
both diagnostics and drugs. Whereas this is currently being addressed for malaria,
monitoring the availability of the active ingredient of a drug in a remote location
is likely to remain a major challenge.

Due to the complexities of coordinating logistics throughout transport chains, only
segments of the transport chain were recorded in this study. A larger study would
likely reveal a wider range of conditions and problems. Since only a small sample
of transport and storage was collected in each country, the results cannot be considered
fully representative of the conditions under which medical commodities are transported
and stored in any of these countries. However, they illustrate the lack of control
in supply chains and potential for environmental damage of products. Ideally, the
condition of RDTs should also have been tested; the countries concerned procure RDTs
with relatively high recommended maximum storage temperatures so it is unclear whether
the relatively short periods when they are exposed to higher temperatures would have
been significant. However, the study results raise concern with respect to RDT stability
between production lots (pre-release real-time testing of production lots is obviously
not possible [1,3], as well as the effect of their co-storage with other perishable medical commodities,
as discussed above.

Conclusion

Transport and storage temperatures varied widely throughout the supply chains monitored
here. In particular high temperatures were recorded at central storage facilities
in some countries. While the recommended storage conditions of the RDTs used by these
health services were rarely exceeded, conditions were inappropriate for many of the
RDTs on the market and frequently exceeded common pharmaceutical storage standards.
A number of simple measures can be instituted to lower ambient temperatures, and tests
for commodity quality control are clearly needed. The results illustrate the importance
of health services understanding their supply chain conditions and matching product
procurement to these. They also suggest that a revisit of standards is indicated for
medical commodities in general in the tropics and sub-tropics, as existing standards
for Climatic Zones III and IV appear inadequate on the basis of this study.

Competing interests

The authors declare they have no competing interests.

Authors’ contributions

AA, DB and EL designed the study protocol and instructions. MM, KO, ID, OG, AG and
SM carried out the monitoring and data collection process. AA and EL carried out the
analysis. AA, SOC, BF, MS, JB, DB and EL drafted the manuscript. All authors have
read and approved the manuscript.

Acknowledgements

We would like to thank the ministries of health, the health facility staff in Ethiopia,
Burkina Faso, Senegal and the Philippines for their support in collecting data for
this study. The study was funded by the Foundation for Innovative New Diagnostics
(FIND), through grants from the Bill and Melinda Gates Foundation and the UK Department
for International Development (DFID).